Thyroid hormone interacts with PPARα and PGC-1 during mitochondrial maturation in sheep heart

2005 ◽  
Vol 289 (5) ◽  
pp. H2258-H2264 ◽  
Author(s):  
Timothy D. McClure ◽  
Martin E. Young ◽  
Heinrich Taegtmeyer ◽  
Xue-Han Ning ◽  
Norman E. Buroker ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cytochrome C ◽  
Target Genes ◽  
Steroid Receptors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Postnatal Maturation

Thyroid hormone (TH) promotes cardiac mitochondrial maturation and substrate metabolism after birth. This regulation involves ligand-dependent binding of nuclear TH receptors to target gene elements. TH also putatively controls genes indirectly by modulating transcription and/or translation of other nuclear steroid receptors and coactivators, such as peroxisome proliferator-activated receptor-α (PPARα) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1). We tested the hypothesis that TH influences PPARα and PGC-1 regulation of metabolic genes during postnatal maturation in sheep heart in vivo. We measured their mRNAs and/or protein levels and downstream targets in left ventricle from lambs: fetal (F), 30-day-old after postnatal thyroidectomy (THY), and 30-day-old euthyroid (Con). Both PPARα and PGC-1 mRNA expression decreased from F to Con, while PGC-1 protein increased substantially and PPARα did not change. THY limited this mRNA response and attenuated the paradoxical postnatal PGC-1 protein elevation but did not alter mRNA levels for PPARα, nuclear respiratory factor-1 and hypoxia-inducible factor-1α. THY promotion in PPARα mRNA did not change PPARα protein or mRNA for PPARα target genes, pyruvate-dehydrogenase kinase 4 ( PDK4) and muscle type carnitine palmitoyltransferase I ( mCPTI). THY reduction in PGC-1 protein occurred, while reducing cytochrome c oxidase and cytochrome c content and decreasing cardiac maximal inherent respiratory capacity. These data imply that TH modulates mitochondrial maturation partly through posttranscriptional control of PGC-1, while any important regulation of PDK4 and mCPTI by change in PPARα protein expression remains doubtful. Also, the paradoxical expression pattern between mRNA and protein, particularly for PGC-1, suggests a feedback control mechanism.

Thyroid hormone is required for the phenotype transitions induced by the pharmacological inhibition of calcineurin in adult soleus muscle of rats

2008 ◽  
Vol 294 (1) ◽  
pp. E69-E77 ◽  
Author(s):  
Nathalie Koulmann ◽  
Lahoucine Bahi ◽  
Florence Ribera ◽  
Hervé Sanchez ◽  
Bernard Serrurier ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Soleus Muscle ◽  
Hormone Deficiency ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Thyroid State ◽  
Novel Approach ◽  
A Subunit ◽  
Calcineurin Inhibition

The present experiment was designed to examine the effects of hypothyroidism and calcineurin inhibition induced by cyclosporin A (CsA) administration on both contractile and metabolic soleus muscle phenotypes, with a novel approach to the signaling pathway controlling mitochondrial biogenesis. Twenty-eight rats were randomly assigned to four groups, normothyroid, hypothyroid, and orally treated with either CsA (25 mg/kg, N-CsA and H-CsA) or vehicle (N-Vh and H-Vh), for 3 wk. Muscle phenotype was estimated by the MHC profile and activities of oxidative and glycolytic enzymes. We measured mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the major regulator of mitochondrial content. We also studied the expression of the catalytic A-subunit of calcineurin (CnA) both at protein and transcript levels and mRNA levels of modulatory calcineurin inhibitor proteins (MCIP)-1 and -2, which are differentially regulated by calcineurin activity and thyroid hormone, respectively. CsA-administration induced a slow-to-fast MHC transition limited to the type IIA isoform, which is associated with increased oxidative capacities. Hypothyroidism strongly decreased both the expression of fast MHC isoforms and oxidative capacities. Effects of CsA administration on muscle phenotype were blocked in conditions of thyroid hormone deficiency. Changes in the oxidative profile were strongly related to PGC-1α changes and associated with phosphorylation of p38 MAPK. Calcineurin and MCIPs mRNA levels were decreased by both hypothyroidism and CsA without additive effects. Taken together, these results suggest that adult muscle phenotype is primarily under the control of thyroid state. Physiological levels of thyroid hormone are required for the effects of calcineurin inhibition on slow oxidative muscle phenotype.

scholarly journals Central leptin regulates heart lipid content by selectively increasing PPAR β/δ expression

2018 ◽  
Vol 236 (1) ◽  
pp. 43-56 ◽  
Author(s):  
Cristina Mora ◽  
Cristina Pintado ◽  
Blanca Rubio ◽  
Lorena Mazuecos ◽  
Virginia López ◽  
...  
Keyword(s):  
Target Genes ◽  
Cardiac Tissue ◽  
Cardiac Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hormone Sensitive Lipase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Gene And Protein Expression ◽  
Tag Accumulation

The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2 µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective upregulation of gene and protein expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ, encoded by Pparb/d) and their target genes, adipose triglyceride lipase (encoded by Pnpla2, herefater referred to as Atgl), hormone sensitive lipase (encoded by Lipe, herefater referred to as Hsl), pyruvate dehydrogenase kinase 4 (Pdk4) and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization. Besides, central leptin decreased the expression of stearoyl-CoA deaturase 1 (Scd1) and diacylglycerol acyltransferase 1 (Dgat1) involved in TAG synthesis and increased the CPT-1 independent palmitate oxidation, as an index of peroxisomal β-oxidation. Finally, the pharmacological inhibition of PPARβ/δ decreased the effects on gene expression and cardiac TAG content induced by leptin. These results indicate that leptin, acting at central level, regulates selectively the cardiac expression of PPARβ/δ, contributing in this way to regulate the cardiac TAG accumulation in rats, independently of its effects on body weight.

scholarly journals Exercise Training-Induced PPARβ Increases PGC-1α Protein Stability and Improves Insulin-Induced Glucose Uptake in Rodent Muscles

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 652 ◽  
Author(s):  
Ju-Sik Park ◽  
John O. Holloszy ◽  
Kijin Kim ◽  
Jin-Ho Koh
Keyword(s):  
Cytochrome C ◽  
Exercise Training ◽  
Protein Stability ◽  
Glucose Uptake ◽  
Citrate Synthase ◽  
Peroxisome Proliferator ◽  
Mitochondrial Enzymes ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor

This study aimed to investigate the long-term effects of training intervention and resting on protein expression and stability of peroxisome proliferator-activated receptor β/δ (PPARβ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), glucose transporter type 4 (GLUT4), and mitochondrial proteins, and determine whether glucose homeostasis can be regulated through stable expression of these proteins after training. Rats swam daily for 3, 6, 9, 14, or 28 days, and then allowed to rest for 5 days post-training. Protein and mRNA levels were measured in the skeletal muscles of these rats. PPARβ was overexpressed and knocked down in myotubes in the skeletal muscle to investigate the effects of swimming training on various signaling cascades of PGC-1α transcription, insulin signaling, and glucose uptake. Exercise training (Ext) upregulated PPARβ, PGC-1α, GLUT4, and mitochondrial enzymes, including NADH-ubiquinone oxidoreductase (NUO), cytochrome c oxidase subunit I (COX1), citrate synthase (CS), and cytochrome c (Cyto C) in a time-dependent manner and promoted the protein stability of PPARβ, PGC-1α, GLUT4, NUO, CS, and Cyto C, such that they were significantly upregulated 5 days after training cessation. PPARβ overexpression increased the PGC-1α protein levels post-translation and improved insulin-induced signaling responsiveness and glucose uptake. The present results indicate that Ext promotes the protein stability of key mitochondria enzymes GLUT4, PGC-1α, and PPARβ even after Ext cessation.

Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

2006 ◽  
Vol 291 (3) ◽  
pp. E536-E543 ◽  
Author(s):  
Chaodong Wu ◽  
Salmaan A. Khan ◽  
Li-Jen Peng ◽  
Honggui Li ◽  
Steven G. Carmella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Flux ◽  
Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

scholarly journals PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sean R. Pyper ◽  
Navin Viswakarma ◽  
Yuzhi Jia ◽  
Yi-Jun Zhu ◽  
Joseph D. Fondell ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Coactivator ◽  
Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

scholarly journals Endocrine-Disrupting Organotin Compounds Are Potent Inducers of Adipogenesis in Vertebrates

2006 ◽  
Vol 20 (9) ◽  
pp. 2141-2155 ◽  
Author(s):  
Felix Grün ◽  
Hajime Watanabe ◽  
Zamaneh Zamanian ◽  
Lauren Maeda ◽  
Kayo Arima ◽  
...  
Keyword(s):  
Steroid Receptors ◽  
Cell Model ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligand ◽  
Tributyltin Chloride ◽  
Environmental Agents ◽  
Adipose Mass

Abstract Dietary and xenobiotic compounds can disrupt endocrine signaling, particularly of steroid receptors and sexual differentiation. Evidence is also mounting that implicates environmental agents in the growing epidemic of obesity. Despite a long-standing interest in such compounds, their identity has remained elusive. Here we show that the persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces the differentiation of adipocytes in vitro and increases adipose mass in vivo. TBT is a dual, nanomolar affinity ligand for both the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor γ (PPARγ). TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased epididymal adipose mass in adults. In the amphibian Xenopus laevis, ectopic adipocytes form in and around gonadal tissues after organotin, RXR, or PPARγ ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPARγ activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Target Gene Encoding a Novel Angiopoietin-Related Protein Associated with Adipose Differentiation

2000 ◽  
Vol 20 (14) ◽  
pp. 5343-5349 ◽  
Author(s):  
J. Cliff Yoon ◽  
Troy W. Chickering ◽  
Evan D. Rosen ◽  
Barry Dussault ◽  
Yubin Qin ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Time Course ◽  
Target Gene ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Isolation And Characterization ◽  
Adipose Differentiation ◽  
Novel Target

ABSTRACT The nuclear receptor peroxisome proliferator-activated receptor γ regulates adipose differentiation and systemic insulin signaling via ligand-dependent transcriptional activation of target genes. However, the identities of the biologically relevant target genes are largely unknown. Here we describe the isolation and characterization of a novel target gene induced by PPARγ ligands, termed PGAR (for PPARγ angiopoietin related), which encodes a novel member of the angiopoietin family of secreted proteins. The transcriptional induction of PGAR follows a rapid time course typical of immediate-early genes and occurs in the absence of protein synthesis. The expression of PGAR is predominantly localized to adipose tissues and placenta and is consistently elevated in genetic models of obesity. Hormone-dependent adipocyte differentiation coincides with a dramatic early induction of the PGAR transcript. Alterations in nutrition and leptin administration are found to modulate the PGAR expression in vivo. Taken together, these data suggest a possible role for PGAR in the regulation of systemic lipid metabolism or glucose homeostasis.

scholarly journals Leptin Rapidly Induces the Expression of Metabolic and Myokine Genes in C2C12 Muscle Cells to Regulate Nutrient Partition and Oxidation

2015 ◽  
Vol 35 (1) ◽  
pp. 92-103 ◽  
Author(s):  
Yuriy Nozhenko ◽  
Ana M. Rodríguez ◽  
Andreu Palou
Keyword(s):  
Time Course ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Muscle Cells ◽  
Pyruvate Dehydrogenase Kinase ◽  
C2c12 Myotubes ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels

Background: Skeletal muscle can experience pronounced metabolic adaptations in response to extrinsic stimuli, and expresses leptin receptor (OB-Rb). We aimed to further the understanding of leptin effects on muscle cells, by studying the expression of key energy metabolism genes in C2C12 myotubes. Methods: We performed a dose-time-dependent study with physiological concentrations of leptin: 5, 10 and 50ng/ml, for 0, 30', 3h, 6h, 12h and 24h, also monitoring time-course changes in non-treated cells. mRNA levels were analyzed by RT-qPCR and peroxisome proliferator activated receptor γ coactivator 1α (PGC1α) protein levels by western blot. Results: The most significant effects were observed with 50ng/ml leptin. In the short-term (30' and/or 3h), leptin significantly induced the expression of PGC1α, muscle carnitine palmitoyl transferase 1 (mCPT1), uncoupling protein 3 (UCP3), OB-Rb, Insulin receptor (InsR) and interleukins 6 and 15 (IL6, IL15). There was a decrease in mRNA levels of pyruvate dehydrogenase kinase 4 (PDK4) and mCPT1 in the long-term (24h). PGC1α protein levels were increased (24h). Conclusion: Leptin rapidly induces the expression of genes important for its own response and the control of metabolic fuels, with the rapid responses of the genes encoding the master regulator PGC1α, mCPT1, UCP3, PDK4 and the signaling secretory molecule IL6 particularly interesting.

scholarly journals The endocrine disruptor mono-(2-ethylhexyl)phthalate promotes adipocyte differentiation and induces obesity in mice

2012 ◽  
Vol 32 (6) ◽  
pp. 619-629 ◽  
Author(s):  
Chanjuan Hao ◽  
Xuejia Cheng ◽  
Hongfei Xia ◽  
Xu Ma
Keyword(s):  
Target Genes ◽  
Adipocyte Differentiation ◽  
Cell Model ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Ethylhexyl Phthalate

The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental ‘window’ contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.

scholarly journals Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3610-3624 ◽  
Author(s):  
Gabriele Schoiswohl ◽  
Maja Stefanovic-Racic ◽  
Marie N. Menke ◽  
Rachel C. Wills ◽  
Beth A. Surlow ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Target Genes ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Peroxisome Proliferator ◽  
Immune Cell Infiltration ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triacylglycerol Hydrolysis

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

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